This invention relates to a system and multiple methods for removing gas from an aqueous solution, and in particular, embodiments for avoiding subdermal hematomas from the use of a needle-less injector when the system and methods are employed in conjunction with the loading of a needle-less injector ampoule.
In an application in which a liquid must be filled into a sealed container, it may be preferable that substantially all gas be removed from the liquid either prior to filling or soon after the container is filled. For example, in filling ampoules with liquid medications for use in a needle-less injector, it may be desirable to de-gas the medication prior to filling the ampoule or, alternatively, for the medication to be de-gassed once the ampoule is filled.
Typically, needle-less medication injections are performed with xe2x80x9cpermanent gunxe2x80x9d instruments, generally referred to as xe2x80x9cjet injectors.xe2x80x9d These devices use either a compression spring or a compressed inert gas to propel the fluid medication (via a push rod plunger) through a small orifice (an injector nozzle) which rests perpendicular to and against the injection site. The fluid medication is generally accelerated at a high rate to a speed of between about 800 feet per second (fps) and 1,200 fps (approximately 244 and 366 meters per second, respectively). This causes the fluid to pierce through the skin surface without the use of a needle, resulting in the medication being deposited in a flower pattern under the skin surface. This method of medication delivery is referred to as a subcutaneous injection.
Medication delivery via needle-less injector periodically results in the formation of subdermal hematomas, and efforts have been made to reduce the likelihood and severity thereof. In U.S. Pat. No. 6,156,008 issued Dec. 5, 2000, we described an injection site detecting device for avoiding subdermal hematomas from an injection, wherein the detecting device is employed prior to injection to locate a site of low blood flow, relative to the surrounding area. Since it is believed that administering a needle-less injection in a region of lower blood flow corresponds to lower bruising potential, utilization of this device reduces the likelihood of causing a subdermal hematoma from administration of an injection with a needle-less injector.
Subdermal hematomas, tissue damage, and scarring from mechanical force injury may also result from the use of needle-less injectors when pockets of gas are present in the injector ampoule prior to dispensing the medication contained therein. Within the 800 to 1200 fps range, optimal for acceleration of liquid medication through the skin via a needle-less injector, liquid readily penetrates the skin while air does not. Thus, gas pockets accelerated against the skin lead to the formation of a bruise and can be quite painful for the recipient, whereas liquid medication passes into and/or through the skin without discomfort.
In general, the gas pocket is found at the dispensing terminus of the ampoule, which is proximate to the skin, though this can change depending on the orientation of the ampoule during storage. Further, when the cap is removed from the end of a needle-less injector, exposing the dispensing area for application to the skin surface, any gas pocket not already situated at the dispensing end may tend to migrate toward that end, due to the pressure change caused by cap removal. This motion of the gas pocket often forces some liquid from the ampoule, thereby diminishing the volume of liquid that will be injected into the recipient. This renders the dosage level inaccurate, as a nontrivial volume of medication is lost from the injector prior to use.
Gas pockets may be present from the outset, resulting from the improper loading of an ampoule. Filling the ampoule with an insufficient amount of liquid clearly leaves such a pocket. However, overfilling the ampoule and removing any excess to arrive at the desired volume is generally not a practical alternative, either, since it is likely that a small amount of liquid will remain on the outer surface of the ampoule. In the medical context, any such liquid is likely to foster the growth of bacteria, which is unacceptable in a scenario where sterile conditions are imperative. Any ampoule with such bacterial growth must be disposed of, and is therefore wasteful.
Even in a perfectly filled ampoule, where no cognizable gas pockets are present immediately following loading, pockets may still develop over time as the dissolved gases present in the liquid separate out from solution. Dissolved gases are naturally present in liquids as a function of the gases"" partial pressures in the local atmosphere. Known to those skilled in the art as Henry""s Law, the concentration of a particular gas in solution is proportional to the pressure of that same gas in the air abutting the solution. Thus, dissolved gases are present in the liquids filled into ampoules under normal conditions (i.e., wherein filling is not performed in a vacuum, or the like) in concentrations proportional to their partial pressure in air. These dissolved gases consist mostly of nitrogen and oxygen, along with several trace gases, and are found latent in the solution in amounts related to their partial pressures in the local atmosphere.
The size of gas pockets varies according to the pharmaceutical active in solution, as some actives allow liquid to retain greater amounts of gas than others, but in some instances a pocket may be as large as 20% of the total ampoule volume. This naturally occurring formation of gas pockets is exacerbated when pre-filled ampoules remain unused for substantial periods of time. Again, varying with the type of active in solution, some actives will form substantial gas pockets after only a few days, while others may not form a pocket for a year or more. For certain medicaments, an ampoule may be stored as long as three to five years, and nearly every active will generate a gas pocket in that amount of time.
Increased temperature also affects the separation of gas from solution, prompting gas pockets to form faster and larger. Pharmaceutical actives generally require storage within a certain optimal temperature range in order to prevent the active from breaking down and thus losing efficacy. For example, many proteins suitable for injection will denature at high temperatures. However, optimal temperature ranges for efficacy may not have any correlation with temperature that would avoid a gas pocket from forming in storage. Thus, one may be forced to choose between either preserving drug efficacy or minimizing gas pocket formation.
In the context of injection by more traditional means such as with a preloaded syringe, it is well established that any significant amount of air in such a device will cause pain for the recipient and potentially far more dire consequences if the amount of air is substantial. Gas pockets may develop in these syringes much in the way described above with regard to ampoules of needle-less injectors, as these devices are frequently subject to similar storage conditions and requirements. Those administering such injections can more readily obviate these limitations, however, as air may be evacuated from the liquid-containing chamber of a syringe by partially depressing the plunger while the syringe is inverted immediately prior to administration of an injection. This is generally not possible with a needle-less injector, as the entire volume of a needle-less injector ampoule is evacuated in one step during normal operation. Moreover, liquid that is inadvertently evacuated from the chamber of a syringe along with the undesirable air does not present a sterility concern, since bacteria will not grow in a pharmacologically hazardous amount in the few moments between evacuating such air and administering an injection. Oftentimes some small quantity of air will remain in the syringe chamber, however, resulting in an injection more painful than would have been had the air been removed by another, more thorough methodology.
It is an object of an embodiment of the present invention to provide a method for removing gas from an aqueous solution.
It is an object of another embodiment of the present invention to provide a method for filling a container with a de-gassed liquid, wherein the liquid contains gas prior to being filled into the container.
It is an object of another embodiment of the present invention to provide a method for filling a container with liquid containing a gas wherein the gas separates out from the liquid such that the liquid becomes de-gassed.
It is an object of yet another embodiment of the present invention to provide a method for avoiding subdermal hematomas in the course of administering needle-less injections, that obviates for practical purposes, the above-mentioned limitations.
The present invention relates to a system and multiple methods for removing dissolved gases from a liquid to be filled into a container that is subsequently filled as well as methods for removing gases from a liquid after a container is filled. One embodiment of the instant invention involves partially filling a tank with gas-containing liquid and applying a vacuum source to an opening in the tank so that the atmospheric pressure above the gas-containing liquid is significantly reduced. In particular embodiments of the invention, the tank may be rotated to facilitate consistent removal of dissolved gases throughout the liquid. In alternative embodiments, the tank may be heated to further facilitate the gas removal process. Once the desired amount of dissolved gas has been removed, the vacuum source may be removed from the tank opening and the tank may be sealed. The tank may then be turned upside down so that the de-gassed liquid is near the opening and the tank may be coupled to filling equipment. Filling equipment may then be used to fill a container, such as the ampoule of a needle-less injector, a syringe, or the like.
The device in this embodiment operates as a function of what is known to those skilled in the art as Henry""s Law, which states that the pressure of a gas abutting a solution is proportional to the concentration of the same gas dissolved in the solution. Thus, as the air pressure in the tank of the present invention is reduced, the concentration of the gases in the solution decreases accordingly. In this embodiment of the present invention, these gases consist mostly of nitrogen and oxygen, and are found latent in the solution in amounts related to their partial pressure in the local atmosphere. However, the system will function in substantially the same manner with other dissolved gases.
Another embodiment of the instant invention involves partially filling a tank with gas-containing liquid and heating the tank. The liquid in the tank is either boiled or warmed to a temperature below its boiling point, while the tank remains open. Once the desired amount of dissolved gas has been removed, the tank opening may be sealed. The tank may then be turned upside down so that the de-gassed liquid is near the opening and the tank may be coupled to filling equipment. Filling equipment may then be used to fill a container, such as the ampoule of a needle-less injector, a syringe, or the like.
Yet another embodiment of the instant invention involves partially filling a tank with gas-containing liquid and resonating sound waves through the liquid, where such waves are originated by the high frequency oscillations at the tip of a device deployed therein. Known to those skilled in the art as xe2x80x9csonicating,xe2x80x9d such a device agitates a liquid and removes gas therefrom, while no harm is caused to a solute dissolved therein. This device may be employed in conjunction with a vacuum, heat, or a combination thereof. Once the desired amount of dissolved gas has been removed, the tank opening may be sealed. The tank may then be turned upside down so that the de-gassed liquid is near the opening and the tank may be coupled to filling equipment. Filling equipment may then be used to fill a container, such as the ampoule of a needle-less injector, a syringe, or the like.
Yet another embodiment of the instant invention involves filling a vacuum-sealed bag with lyophilized solute, or another solute in either liquid or solid form. De-gassed water or another appropriate de-gassed solvent may then be added to the bag, with the resulting solution being substantially free of dissolved gas. The bag can then be coupled to filling equipment and used to fill a container, such as the ampoule of a needle-less injector, a syringe, or the like.
Yet another embodiment of the instant invention involves partially filling a tank with gas-containing liquid and percolating another gas through the liquid. Concurrently, a vacuum is applied to the interior atmosphere of the tank such that a portion of the percolating gas is removed, along with a portion of the gas that was formerly dissolved in the liquid. The rate of addition of percolating gas to the system may be less than, equal to, or greater than the rate at which gas is removed from the tank via the vacuum source, such that a user may additionally utilize a pressure differential to drive gas out of the liquid. Once the desired amount of dissolved gas has been removed from the liquid, displaced by the percolating gas, the vacuum source and percolating gas line may be removed from the tank and the tank may be sealed. The tank may then be turned upside down so that the percolating gas-containing liquid is near the opening and the tank may be coupled to filling equipment. Filling equipment may then be used to fill a container, such as the ampoule of a needle-less injector, a syringe, or the like. The percolating gas may remain dissolved in the liquid after a container is filled therewith. Of the two types of preferred percolating gases, one type diffuses out of the container directly through the walls thereof, while the other type bonds or otherwise chemically reacts with a part of the container or other mechanical structure in contact with the liquid or chemical lining on the interior of the container, such that the gas extracts itself from the liquid. Preferably, the gas does not change phase during this bonding or other reaction.
Yet another embodiment of the instant invention involves xe2x80x9csalting outxe2x80x9d the dissolved gas from a liquid to be filled into a container. Along with any desirable solute, a salt or buffer is added to a liquid at a sufficiently high concentration such that substantially no gas can remain in the concentrated solution. The solution can be filled via filling equipment into a container, such as the ampoule of a needle-less injector, a syringe, or the like. The solution can further be diluted with de-gassed water or another suitable de-gassed liquid either prior to filling into a container, immediately after filling into a container, or at a later time such as just before administration of an injection with a needle-less injector.
Yet another embodiment of the instant invention involves a process similar to xe2x80x9csalting out,xe2x80x9d however in this embodiment the solute itself (e.g., a pharmaceutical active) is present in the liquid in such a high concentration that substantially no gas can remain in the liquid. The solution can be filled via filling equipment into a container, such as the ampoule of a needle-less injector, a syringe, or the like. The solution can further be diluted with de-gassed water or another suitable de-gassed liquid either prior to filling into a container, immediately after filling into a container, or at a later time such as just before administration of an injection with a needle-less injector.
Yet another embodiment of the instant invention involves an absorbent material being held in a compartment external to the container, where only gaseous communication exists between this compartment and the interior of the container. The liquid contains a gas that is absorbed by the material contained in the compartment, such that the liquid de-gasses after the container is filled.